A variety of catalytic methods have been described for the preparation of biaryl compounds or for the coupling of alkyl or alkenyl radicals to an aryl group. Reviews of these methods can be found in, for example, Stanforth, Tetrahedron, vol. 54 (1998) pp. 263-303; Sainsbury, Tetrahedron, vol. 36 (1980), pp. 3327-3359 and Bringman et al., Angew. Chem. Int. Ed. Engl., vol. 29, (1990), 977-991.
In the field of biaryl couplings, the renaissance began in the mid- to late-1970's with the Kharasch reaction in which an aryl Grignard reagent (Ar′MgX, wherein X is halogen) is reacted with an aryl halide (ArX) to produce a biaryl (Ar—Ar′) compound. However, a number of functional groups (e.g., aldehydes, ketones, esters and nitro groups) are not compatible with conditions for the Kharasch reaction.
Tamao et al., Bull. Chem. Soc. Japan, vol. 49 (1976), pp. 1958-1969, discloses that arylbromides can be reacted with arylmagnesium halides (aryl Grignard reagents) in the presence of dihalodiphophinenickel complexes to give biaryl compounds. A sole disclosed attempt to react an aryl chloride (chlorobenzene) with an arylmagnesium halide (mesityl) was reported to give only a 6% yield of the desired biaryl. Similar reactions of the bromobenzene with mesitylmagnesium bromide gave yields of 78-96%. This reference states, “The most serious limitation is that the substituents on the organic halides and on the Grignard reagents are restricted to those which cannot react with Grignard reagents.”
Clough et al., J. Org. Chem., vol. 41 (1976), pp. 2252-2255 disclose that 1,8-dihalonapthalenes can be reacted with arylmagnesium halides in the presence of certain soluble nickel catalysts to give 1,8-diarylnaphthalenes. The reactivities of the 1,8-dihalonaphthalenes in this system was found to be I>Br>>Cl.
U.S. Pat. No. 4,912,276 discloses that aryl chlorides can be reacted with arylmagnesium halides in the presence of a nickel-triorganophosphine catalyst to give biaryl compounds. The disclosed scope of the aryl groups in the arylchlorides, the arylmagnesium reagents, and the biaryl compounds consists of phenyl and substituted phenyl in which the substituents are those that have previously demonstrated a lack of reactivity with arylmagnesium halides (e.g., alkyl, alkoxy and the like). The only biaryl whose preparation is exemplified by working examples is the symmetrical biaryl 2,2′dimethylbiphenyl, prepared from 2-chlorotoluene and o-tolylmagnesium chloride (derived from 2-chlorotoluene).
Pridgen, J. Org. Chem., vol. 47 (1982), pp. 4319-4323 discloses two examples in which 2-(chlorophenyl)-2-oxazolines are reacted with arylmagnesium halides in the presence of a diphosphine-chelated nickel catalyst to give the corresponding 2-(biaryl)-2-oxazoline compounds. The oxazoline group activates the aryl chloride and provides a form of the carboxyl group that is protected from reaction with the arylmagnesium halide.
U.S. Pat. No. 5,288,895 describes a process for the preparation of 4-methyl-2′-cyanobiphenyl (a.k.a. 2-(4′-methylphenyl)benzonitrile) wherein a 2-halobenzonitrile is reacted with a 4-methylphenyl magnesium halide in the presence of manganous salt. The patent provides examples in which 2-chlorobenzonitrile produces a coupled product (2-(4′-methylphenyl)benzonitrile) with a yield of 60-75% recovered as a “brown viscous liquid”. Recrystallizations (plural) are reported to give the product as a beige solid, but the yield of this purified solid is not reported.
Negishi followed Kharasch's work in the mid 1970's with a coupling reaction in which an aryl zinc reagent (Ar′ZnX, wherein X is halogen) is reacted with an aryl halide or triflate (ArX, wherein X is halogen or triflate) to produce a biaryl (Ar—Ar′) compound. The zinc reagents used by Negishi are generally more tolerant of functional groups such as esters, aldehydes and ketones. In particular, Negishi et al, J. Org. Chem., vol. 42 (1977), pp. 1821-1823 discloses reactions of arylzinc derivatives (arylzinc chloride or diarylzinc) with aryl bromides or iodides in the presence of nickel or palladium complexes as catalysts to produce unsymmetrical biaryls. The arylzinc derivatives were prepared by a metathesis reaction between the corresponding aryllithium and zinc dichloride. Additionally, the authors note the ability of arylzinc derivatives to tolerate various electrophilic functional groups, such as nitrile and ester, in the arylbromide or iodide.
Zhu et al., J. Org. Chem., vol. 56 (1991), pp. 1445-1453 similarly disclose reactions of arylzinc halides with aryl bromides or aryl iodides in the presence of a palladium tetrakis(triphenylphosphine as catalyst to form biaryl compounds. The arylzinc halides were prepared by the reaction of the arylhalide with a form of highly reactive zinc.
Silbille et al., J. Chem. Soc. Chem. Comm., 1992, pp. 283-284 disclose a reaction of 4-trifluoromethylphenylzinc chloride, prepared from 4-trifluoromethyl-chlorobenzene, with 4-bromobenzonitrile using the palladium complex PdCl2(PPh)3)2 as catalyst to form 4-trifluoromethylphenyl-4′-cyanobiphenyl. This reference also discloses a method of preparing arylzinc halides from arylchlorides and arylbromides, including arylzinc reagents ones bearing various functional groups such as ester, nitrile, or ketone.
Carini et al., J. Med. Chem., vol. 34 (1991), 2525-2547, disclose the preparation of 3-(4′-methylphenyl)benzonitrile by reacting 4-methylphenylzinc halide (prepared from 4-bromotoluene via 4-methylphenylmagnesium bromide, which is reacted with zinc chloride) and 3-bromobenzonitrile in the presence of bis(triphenylphosphine)nickel dichloride as precatalyst. U.S. Pat. No. 5,128,355 (to Carini et al.) similarly shows an equation (Scheme 14, Equation e) representing the nickel catalyzed cross coupling of a methylphenylzinc chloride (isomer unspecified) with a bromobenzonitrile (isomer unspecified) to give a methylphenylbenzonitrile (isomer unspecified). This method is exemplified only for the preparation of 2,6-dicyano-4′-methylbiphenyl from 2,6-dicyanophenylbromide (Example 343).
Mantlo et al., J. Med. Chem., vol. 34 (1991), pp. 2919-2922 discloses the preparation of 2-(4′-methylphenyl)benzonitrile from 4-bromotoluene and 2-bromobenzonitrile according to the method (referenced) of Negishi et al. J. Org. Chem., vol. 42 (1977), pp. 1821-1823. A zinc derivative was formed from the 4-bromotoluene and reacted with the 2-bromobenzonitrile in the presence of a catalytic amount of a dichlorobis(triphenylphosphine)nickel.
By the late 1970's Stille had extended the biaryl coupling repertoire to include the reaction of arylstannanes (Ar′SnR3, wherein R is methyl or butyl) with aryl halides or triflates (ArX, wherein X is halogen or triflate). While this reaction can be run under neutral conditions and is generally compatible with a wide range of aryl substituents, the toxicity of the organotin reagents and byproducts limits the usefulness of this method.
More recently, Suzuki and coworkers developed a coupling reaction in which an aryl boronic acid (Ar′B(OH)2) is reacted with an aryl halide or triflate (ArX, wherein X is halogen or triflate) to produce the biaryl product Ar—Ar′. An early report of this general reaction is Miyaura et al., Synthetic Communications vol. 11 (1981), 513. In this reference, chlorobenzene is reported to fail to react with phenylboronic acid using tetrakis(triphenylphosphine)palladium as catalyst in this system.
Ali et al., Tetrahedron, vol 48 (1992), pp. 8117-8126 disclose Suzuki-type cross-coupling reactions of arylboronic acids with pi-electron deficient heteroaryl chlorides (chloropyridines, chloropyrimidines, and chloropyrazines, chloroquinolines).
U.S. Pat. No. 5,130,439 discloses a process for preparing certain protected tetrazolyl biphenyls in which a protected tetrazolylphenylboronic acid or boronate derivative is reacted with a substituted phenyl bromide or iodide or a substituted sulfonyloxyphenyl derivative in the presence a base and a nickel, palladium or platinum catalyst, preferably palladium. Three of the working examples (Examples 4, 9, and 12) relate to the disclosed process for preparing the protected tetrazolyl biphenyls, and all involve reactions of triphenylmethyltetrazolylphenylboronic acid with a substituted (4-methyl, 4-hydroxymethyl, 4-formyl) bromobenzene in the presence of a tetrakis(triphenylphosphine)palladium catalyst and a carbonate base. This process has the disadvantage of requiring prior synthesis of the triphenylmethyltetrazolylphenylboronic acid. This reference discloses a process for preparing the triphenylmethyltetrazolylphenylboronic acid from the corresponding bromobenzonitrile by reacting it with tributyltin chloride and sodium azide, then with triphenylmethyl chloride to form the triphyenylmethyltetrazolylphenylbromide, which is reacted sequentially with n-butyllithium and triisopropylborate and the resulting boronate ester is finally hydrolyzed to the boronic acid. This reference illustrates that the nitrile group must be protected, in this case as the triphenylmethyltetrazolyl group, to be compatible with the use of an aryllithium intermediate in the overall process.
European Patent Application 470,795 discloses a process for preparing biphenylcarbonitriles in which a 4-methylphenyl boronic acid or boronate ester is reacted with a bromo-, iodo-, or trifluoromethanesulphonyloxy-benzonitrile in the presence of a palladium or nickel catalyst and a suitable base. Three of the working examples (Examples 1, 2, and 6) relate to the disclosed process for preparing biphenylcarbonitriles, and all involve reactions of the 4-methylphenylboronic acid with 2-bromobenzonitrile in the presence of a palladium catalyst and sodium carbonate.
Saito et al., Tetrahedron Letters, vol 37 (1996), pp. 2993-2996 states, “The palladium-catalyzed cross-coupling reaction of arylboronic acids with aryl halides or triflates gives biaryls. High yields have been achieved with many substrates having various functional groups on either coupling partner, when using aryl bromides, iodides, or triflates as an electrophile. Chloroarenes are an economical and easily available, but they have been rarely used for the palladium catalyzed cross coupling reaction of arylboronic acids because of the oxidative addition of chloroarenes is too slow to develop the catalytic cycle. However, chloroarenes have been an efficient substrate for the nickel catalyzed cross coupling reaction with Grignard reagents . . . developed by Kumada and Tamao.” This reference (Saito et al.) discloses syntheses of unsymmetrical biaryls by a nickel(0) catalyzed reaction of arylchlorides with arylboronic acids and tripotassium phosphate as the base at elevated temperatures.
U.S. Pat. No. 5,559,277 discloses a process for preparing biaryls by the Suzuki reaction of haloaromatics or arylsulfonates with arylboronates in the presence of a base and certain specific palladium compounds as catalysts. In addition to numerous bromoaromatics, reactions of chloroacetophenone and 2-chlorobenzonitrile are shown in working examples. All the working examples use at least 50% mole excess of the arylboronate relative to the haloaromatic and conduct the reaction for 16 hours at 130° C. The disclosed process also has the disadvantage of requiring the separate preparation of the arylboronate. Example 7 describes the preparation of 2-cyano-4-methylbiphenyl (a.k.a. 2-(4′-methylphenyl)-benzonitrile) from 2-chlorobenzonitrile and 4-methylphenylboronic acid in 73% yield (49% yield on the 4-methylphenylboronic acid).
Kalinin, Synthesis, 1992, 413-432 reviews carbon-carbon bond formation to heteroaromatics using nickel and palladium catalyzed reactions and provides numerous examples of the formation of unsymmetrical biaryls, wherein at least one of the aryl groups includes a heteroatom, including examples of palladium catalyzed reactions of arylbromides and aryliodides with arylzinc halides, palladium catalyzed reactions of chloropyridines with arylmagnesium halides, and nickel catalyzed reactions of arylchlorides and arylbromides with arylmagnesium halides.
U.S. Pat. No. 5,364,943 discloses the preparation of 3-amino-2-phenylpyridine and two 3-(substituted benzylamino)-2-phenylpyridine derivatives by the reaction of the corresponding 3-amino-2-chloropyridine or N-benzyl derivative with phenyl magnesium bromide in the presence of bis(phosphine)nickel dichloride complexes. For the parent compound (Example 7), a total of 4.4 eq. of phenylmagnesium bromide was reacted with 3-amino-2-chloropyridine and 0.5 eq. [bis(diphenylphosphino)ethane] nickel(II) chloride over the course of two days, to ultimately obtain a 48% of the isolated product.
Despite the early success with many of these coupling reactions and the continued efforts to refine and extend their applications, further efforts have focused on extending the coupling reactions to multigram or kilogram quantities and to manipulating reaction conditions to increase yields and provide alternatives to the limitations observed with each of the methods described.
For example, in 1998, Miller and Farrell described the preparation of unsymmetrical biaryl via Ni- or Pd-catalyzed coupling of aryl chlorides with arylzincs (see, Miller and Farrell, Tetrahedron Letters 39:6441-6444 (1998)). This extension of the Negishi reaction utilized the less expensive and readily available aryl chlorides. See also Miller and Farrell, U.S. Pat. No. 6,194,599 B1, issued Feb. 27, 2001.
Miller and Farrell continued their examination of biaryl couplings, particularly those with reactive functional group substituents. Biaryl compounds having functional groups such as nitriles or esters were efficiently synthesized by the direct Ni- or Pd-catalyzed cross-coupling of aryl halides with arylmagnesium or -lithium reagents (ArM) provided that a catalytic amount of a Zn or Cd salt is also present. See, Miller and Farrell, Tetrahedron Letters, 39:7275-7278 (1998) and U.S. Pat. No. 5,922,898, issued Jul. 13, 1999.
Despite these advances, methods for aryl or organometallic couplings on benzonitriles wherein the nitrile group is displaced by the aryl or alkyl portion of an organometallic reagent have not been described. In view of the ready availability of benzonitrile derivatives, such methods would find considerable usefulness in extending the scope of couplings that are currently in use.
Surprisingly, the present invention provides such methods.